Project Summary The rise of antibiotic resistant pathogens in the clinic is undeniably a recognized medical concern since it is the cause of enormous human and economic loss worldwide. Of further alarm is the lack of new therapeutics to combat these harmful and potentially deadly infections. Accordingly, it is critical that we generate novel approaches to address this growing problem. The development of reagents that enhance host immunity may be an effective alternative strategy to promote host resistance to infection by reducing pathogen numbers. In addition, identifying mechanisms that can support host tolerance to withstand the damage inflicted by harmful microbes and the inflammatory response is equally as vital. Mitochondria have multiple essential cellular functions including a recognized role in mediating the immune response. The mitochondrial unfolded protein response (UPRmt), a stress-activated pathway that recovers mitochondrial function, also participates in host defense against infection through the regulation of innate immunity. Further investigation into the regulation and therapeutic potential of the UPRmt is therefore warranted considering its dual roles in preserving mitochondrial homeostasis and inducing anti-microbial defense. The current proposal will explore the UPRmt in the context of pathogen infection to uncover novel mechanisms of its regulation by both the host and the infectious agent. Here we will employ a combined approach using the powerful genetic model organism Caenorhabditis elegans and the opportunistic bacterial pathogen Pseudomonas aeruginosa, an established system in the study of host-microbe interactions. Moreover, we will build on our current understanding by evaluating the potential role of the mammalian UPRmt in promoting host survival during infection. Collectively, the outcomes from our proposed research plan are expected to yield novel insights of the UPRmt during infection that potentially may be used to enhance host protection during infection.